Chemical process and products produced thereby



United States Patent 3,272,880 CHEMICAL PROCESS AND PRODUCTS PRODUCED THEREBY Norman L. Wendler, Summit, and David Taub, Me-

tuchen, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed July 24, 1962, Ser. No. 212,144

2 Claims. (Cl. 260668) This invention relates to a process for making intermediates for the synthesis of H-dibenZo-[a,d]-cycloheptenes which are substituted at the S-carbon atom with an aminopropyl radical. The invention also includes the synthesis of certain novel compounds produced by said process.

The aminopropyl compounds which are formed from the intermediates of the present invention are useful in the treatment of mental health conditions as they are antidepressants and serve as mood elevators or psychic energizers. These compounds are preferably administered in the form of their acid salts and these salts are included in the scope of this invention.

The process of the present invention may be represented by the following flow sheet.

Y Y A i X 1 X X X ZHal H M H Z Utility, S.N. 188,873, filed April 19, 1962; S.N. 209,311, filed July 12, 1962.

Dibenzocycloheptenes Sl1bstituted at the 5carb)n atom with an ammopropyl radical.

in which M is a metal, such as lithium, sodium or potassium in which Hal is a halogen, preferably chlorine or bromine; Y is a halogen or hydrogen; Z is allyl and a 1', 2' and 3'-alkyl-substituted allyl, and X and X are similar or dissimilar and are selected from the group consisting of hydrogen, an alkyl group having up to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perfiuoroacylamino group having up to 4 carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms, halogen (fluorine, chlorine, bromine or iodine), hydroxyl, an allcoxyl group having up to 4 carbon atoms, a perfiuoroalkoxyl group having up to 4 carbon atoms, cyano, carboxy, carbamyl, an alkylcarbamyl group having up to 5 carbon atoms, a dialkylcarbamyl group having up to 9 carbon atoms, a carbalkoxy group having up to 6 carbon atoms, mercapto, and alkylmerc'apto group having up to 4 carbon atoms, a perfiuoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, a perfluoroalkylsulfonyl group having up to 4 carbon atoms, sulfamyl, an alkylsulfamyl group having up to 4 carbon atoms, or a dialkylsulfamyl group having up to 8 carbon atoms; more than one of these substituents may be on each benzenoid ring.

The method of the present invention begins with the S-metallo derivative of a 5H-dibenzo-[a,d]-cycloheptene which may be prepared by a process described by Villani et al., in the Journal of Medicinal & Pharmaceutical Chemistry 5, 373 (1962). These compounds are prepared, for example, from the known 5H-dibenzo-[a,d]- cycloheptene-S-ones which, in turn, may be prepared by using the process described by A. C. Cope et a1. entitled, Cyclic Polyolefins, XV, 1-methylene-2,3,6,7-dibenzocycloheptatriene, appearing in the J.A.C.S., 73, 1673 to 1678 (1951). The starting compounds for the ketones, and particularly those having substituents on the benzene rings, may be made by following the teachings of T. W. Campbell et al. in an article entitled Synthesis of 2- acetamido-2,3,6,7-dibenzotropilidene and 2-acetamido-9,9- dimethylfluorene, appearing in Helv. Chem. Act-a, 36, 1489 to 1499 (1953). Starting ketones for the Y-substituted compounds may be made following the teachings of Treibs and Klinkhammer in the Chemische Berichte, 84, 671 (1951); Villani et al., Journal of Medicinal & Pharmaceutical Chemistry, 5, 373 (1962); Provita et al., Journal of Medicinal & Pharmaceutical Chemistry, 4, 411 (1961), and the references cited therein.

As shown in the How sheet above, the method of the present invention involves the condensation of a S-metallo- 5H-dibenzo-[a,d]-cycloheptene with an allyl or a 1, 2 and 3'-alkyl substituted allyl halide to form the corre sponding 5-allyl-5H-dibenzo-[a,d]-cycloheptene. In a typical run, S-lithio-SH-dibenzo-[a,d]-cycloheptene is reacted With allyl bromide in dry diethyl ether under reflux to form 5-allyl-5H-dibenzo-[a,d]-cycloheptene.

Once the 5-allyl-5H-dibenzo-[a,d]-cycloheptene is obtained, it may be utilized as an intermediate to form the useful dibenzocycloheptenes substituted at the S-carbon atom with an aminopropyl radical in accordance 'with the processes described in copending applications and, specifically, following the teachings described in S.N. 209,311, filed July 12, 196 2 that the S-allyl intermediate is converted to the corresponding S-(yahydroxypropyl)-5H-dibenzo-[a,d]-cycloheptene by addition of a suitable boron compound across the double bond of the allyl group followed by oxidation and hydrolysis of the added boron group to form the desired hydroxy compound. For example, upon treatment of S-allyl-SH-dilbenzo-[a,d]-cycloheptene in ether solution with one mol equivalent of a borane, followed !by oxidative hydrolysis, there is produced the corresponding 5-('y-hydroxypropyl)- SH-dibenzo-[a,d]-cycloheptene.

The hydroxy intermediates then are converted to the aminopropyl compounds by a process of halogenation with a hydrogen halide to produce the corresponding halide derivative, and amination (With an amine to form the desired end product or S-aminopr-opyl derivative. These steps are described in the copending application, Serial Number 188,873, filed April 19, 1962.

The examples which follow will more specifically illustrate the process of the present invention.

EXAMPLE I 5-allyl-5H-dibenz0-[a,d]-cycl0/zeptene A solution of potassium amide (0.1 mole) prepared from 4.2 g. of potassium in 400 cc. of liquid ammonia with ferric chloride catalysis (see Villani et al., Journal of Medicinal & Pharmaceutical Chemistry, 5, 383 (1962)), is treated with a solution of 20 g. of SH-dibenzo-[a,d]-cycloheptene in 400 cc. of ether droplwise over a period of 1 hour. The ammonia is allowed to evaporate and the resulting ether solution is refluxed with stirring for 1-2 hours. At the end of this period, the solution is cooled and a solution of 15 g. (0.2 mole) of allyl chloride is added dropwise and the reaction mixture refluxed for 4 hours. Ice-water is added, the organic layer separated and washed neutral with Water. Evaporation of the solvent yields 5-allyl-5H-dibenzo-[a,d]-cycloheptene.

296 m Efi 510 Following the procedure described in detail above and using starting compounds having X, X and Y substituents as presented above, there are produced the corresponding X, X and Y-substituted S-allyl-SH-dibenzo-[a,d]-cycloheptenes.

EXAMPLE II Following the procedure described in detail in the above examples and using equivalent quantities of 1, 2' and 3wmethyl and ethyl substituted allyl chloride in place of allyl chloride, there are produced the corresponding References Cited by the Examiner Berichte, 832367-71 (1950). Royals, Advanced Organic Chemistry (1954) P ubl. by Constable and Co., London, pp. 119-120.

DELBERT E. GANTZ, Primary Examiner.

ALPHONSO D. SULLIVAN, Examiner.

J. E. DEMPSEY, C. R. DAVIS, Assistant Examiners. 

1. A METHOD OF MAKING A 5-ALLYL-5H-DIBENZO-(A,D)-CYCLOHEPTENE WHICH COMPRISES REACTING A 5-METALLO-5H-DIBENZO-(A,D)-CYCLOHEPTENE WITH AN ALLYL HALIDE. 